This research program will conduct a randomized, controlled, multi-site clinical trial of novel investigative therapeutic technology and methods for treating chronic pain in patients refractory to prior treatment modalities to: training the patients to control their chronic pain using real-time functional magnetic resonance imaging (rtfMRI). This work is the logical extension toward the FDA regulatory process of a successful, ongoing technology-transfer effort that has brought rtfMRI from the research setting into the clinical setting and that has demonstrated positive results in treating chronic pain patients. These investigations further the NIH mission by advancing understanding of distributed brain mechanisms of pain and by definitively testing a novel therapeutic modality for alleviating a condition which is responsible for substantial human suffering and healthcare cost. We have hypothesized that it is possible to train chronic pain patients to control activation in the brain's pain processing areas using rtfMRI, thereby leading to decreased pain. Multiple experiments now support that both experimentally-induced pain and chronic pain in patients can be significantly decreased using this methodology. We will use rtfMRI technology to train chronic pain patients to control activation in the brain's pain system, specifically in a region in the rostral anterior cingulate cortex (rACC) involved in pain perception and control. Previous work from a number of groups has now established that human subjects can learn to control brain activation using rtfMRI. Studies funded through the Phase II grant upon which this application is based have successfully demonstrated that control over brain activation achieved using rtfMRI-based training can lead to control over pain in both healthy subjects and chronic pain patients. Healthy subjects who received training guided by rtfMRI learned increased control over pain perception during a nociceptive stimulus. This control over pain was statistically significantly greater than for several different control subject groups that did not receive rtfMRI training. Chronic pain patients were also able to produce decreases in their pain using rtfMRI-based training greater than controls. An initial clinical trial in chronic pain patients who were trained using rtfMRI over six weeks has demonstrated that long-term decreases in chronic pain can be achieved. The purpose of the newly-created NIH SBIR Phase II Competitive Renewal grant process is to provide continued funding support for promising, NIH-funded technology projects that will incur substantial costs to move through clinical trials supporting the FDA regulatory process. This application proposes a definitive clinical trial of this technology for treating chronic refractory pain patients using rtfMRI in preparation for FDA approval. Clinical trials of pain therapeutics are necessarily large because there is large variability in pain symptoms;small trials often waste resources because they don't have adequate power. This trial will be conducted at leading fMRI research centers (Stanford, MIT, and Omneuron) with similar size to other pain therapeutics trials (N=72 per group, 36 per sub-group), and including a blind, randomized placebo control.